Solid-Phase Synthesis of 3,4,5-Substituted 1,5-Benzodiazepin-2-ones

Abstract

The preparation of 3,4,5-substituted 8-carboxamido-1,5-benzodiazepin-2-ones using a solid-phase synthetic method is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the aryl fluoride with either an alpha- or beta-substituted beta-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group is accomplished in the presence of SnCl(2).H(2)O. Hydrolysis of the ester is carried out in the presence of a heterogeneous mixture of 1 N NaOH/THF (1:1). The resulting aniline acid is cyclized to form the benzodiazepinone skeleton with DIC and HOBt. Selective alkylation at the N-5 position of the benzodiazepinone is accomplished with alkyl halides in the presence of K(2)CO(3) in acetone. The desired products are cleaved from solid supports and obtained in 46-98% isolated yields.

Solid-phase synthesis of isoalloxazines using merrifield resin

“…The reaction of substituted amines/anilines 4a-l with 3 was carried out in DMF to get 4-(N-substituted amino)-3-nitrobenzoate (5a-l). 22 The reduction of 5a-l with SnCl 2 .H 2 O gave resin bound diamines 6a-l. 22 The each nucleophilic substitution products and the diamino products were cleaved with hydrofluoric acid (HF) in DMF and show satisfactory elemental analysis. The cyclocondensation of 6a-l with alloxan monohydrate (7) in the presence of boric acid/acetic acid and DMF gave the resin bound isoalloxazines 8a-l (Scheme 1).…”

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

“…From the spectroscopic data of the final products, no evidence was found for C-and/or O-alkylation. In 1999, the same approach was reported by Lee, with an application of the Rink amide resin and β-amino acid methyl esters [68]. Note that the authors did not manage to cyclize the benzodiazepine scaffold via the intramolecular aminolysis of the ester functionality; therefore, the subsequent hydrolysis and HOBt cyclization had to be performed.…”

HPLC enantioseparation of β2‐homoamino acids using crown ether‐based chiral stationary phase

“…2) were synthetized in two steps from methyl cyanoacetate, which in the first step was either alkylated [24] or condensed with aromatic aldehydes [25,26], and in the next step reduced (and N-protected). (S)-1, (S)-5, and (S)-6 were generous gifts from Professor D. TourwØ (Vrije Universiteit Brussels, Brussels, Belgium).…”